The ability of the T lymphocyte population to distinguish between "self" and "non-self" is the central characteristic of the immune system. Positive selection of self-MHC-restricted T cell clones, and negative selection of auto-reactive T cell clones occur in the thymus, and operate on distinct developmental stages of the CD4+8+ TcR/CD3+ thymocyte subset. Positive selection appears to involve the rescue of self-MHC-restricted cells from a process of pre-programmed cell death known as apoptosis Negative selection, in contrast, appears to involve the re-activation or re-induction of apoptosis in cells that had previously been rescued during positive selection. An important new component to the regulation of apoptosis in thymocytes is a "protective" mechanism that-can spare thymocytes from apoptosis. The activation of this protective mechanism may therefore be critical for positive selection, and its inactivation may be critical for negative selection. Thus, analysis of both apoptosis and protection from apoptosis can be used as a model to investigate the regulation of T cell repertoire selection. This project has three Specific Aims, asking the following questions: 1. How do TcR signals regulate apoptosis and protection during positive and negative selection? 2. How do non-TcR signals regulate apoptosis and protection during positive and negative selection? 3. What is the intrathymic CD4 ligand that regulates the ability of immature thymocytes to respond to TcR engagement? These studies should contribute to a better understanding of positive and negative selection in the immune system, and could therefore facilitate clinical strategies designed to regulate lymphoid growth and development, such as antigen-specific therapies for anti-tumor responses, transplantation rejection and autoimmune responses, since in each of these cases, an "inappropriate" T cell repertoire is the cause of the clinical difficulty.